Understanding normal and dysfunctional energy balance and body weight regulation requires neural evaluation of the signals involved in the control of food intake within a meal, as well as signals related to the availability of stored fuels. Because ingested nutrients stimulate multiple gastrointestinal sites simultaneously, evaluating the neural representation of combinations of meal-related stimuli is critical to the characterization of putative negative feedback signals that mediate the control of food intake. In the proposed studies, we outline neurophysiological experiments designed to elucidate the neuro-humoral basis of energy balance. These experiments will: 1) identify and characterize short term meal-related gut neurophysiological signals, 2) determine their representation and integration at peripheral vagal, non-vagal and central brainstem nervous system sites, and 3) evaluate how they are interpreted in the context of the neuro-humoral signals related to the long-term control and mobilization of stored fuels. We will focus on the sensory vagus and splanchnic nerves and their central nervous system projections as the main neuroanatomical pathways linking the upper gastrointestinal sites exposed to nutrients during a meal and the central nervous system sites mediating the control of food intake. We will characterize vagal and splanchnic afferent responses to meal-related stimulation of the stomach and duodenum, and determine the extent to which these responses are modulated by administration of gut-brain peptides and neurotransmitters normally released by the duodenal presence of nutrients. Using single unit extracellular neurophysiological recordings, we will assess the neural brainstem representation of signals arising from meal-related stimulation of multiple alimentary tract compartments, including the stomach and duodenum. To characterize the ability of the brainstem to integrate long- and short-term energy balance signals, we will also determine how central administration of putative long-term energy balance peptides modifies meal-related brainstem neurophysiological signals from the gut. This systematic assessment of meal-related peripheral neural activity, its brainstem neural representation, and its integration with putative energy balance peptide signals represent a synthetic evaluation that will significantly advance our understanding of neuro-humoral interactions in the metabolic control of food intake.